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Biomedical subjects

R W Fuller

Publications and source records attributed to R W Fuller.

At least 163 records · Page 9Linked to original sources
PubMed1990

Depletion of cardiac norepinephrine but not brain catecholamines by MPTP-N-oxide in mice.

After a single dose in mice, MPTP-N-oxide caused a dose-dependent depletion of cardiac norepinephrine which was similar although less pronounced than that caused by MPTP itself. After repeated daily doses, MPTP-N-oxide depleted cardiac norepinephrine, but did not deplete norepinephrine in the frontal cortex or dopamine in the striatum of mice. MPTP-N-oxide differed from MPTP, which depleted cardiac norepinephrine, cortical norepinephrine and striatal dopamine after repeated daily doses, but was similar to MPP+, another metabolite of MPTP, which depleted only cardiac norepinephrine. These data suggest that MPTP-N-oxide may contribute to the peripheral catecholamine-depleting effects after MPTP injection.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

Leukotriene C4 elimination and metabolism in man.

Three doses of radiolabeled leukotriene C4 (0.2 to 15 muCi) were infused into three subjects to investigate its metabolism and routes of elimination during 4 days. Between 12% and 20% of the infused dose was recovered in the urine within 24 hours, of which a substantial and relatively constant proportion (4.1% to 6.3% total dose) appeared as leukotriene E4 (LTE4), mainly in the first 4 hours. Polar omega-oxidation products, N-acetyl LTE4, and tritiated water were also present. Fecal elimination accounted for a further 30% to 40% of the infused dose. In the absence of altered metabolism or biliary excretion, urinary LTE4 may be a useful measure of whole body production of the cysteinyl leukotrienes.

Adult↗
PubMed1990

Increased production of cysteinyl leukotrienes in hepatorenal syndrome.

The cysteinyl leukotrienes C4 and D4 are potent renal vasoconstrictors which may modulate glomerular function in vivo, and may therefore be important in the pathogenesis of hepatorenal syndrome. Urinary leukotriene E4, the major metabolite of leukotrienes C4 and D4, was elevated in patients with hepatorenal syndrome (17.8 ng/h) when compared with normal controls (5.1 ng/h) or subjects with renal failure alone (1.9 ng/h). Urinary leukotriene E4 was also elevated in subjects with decompensated liver disease (cirrhosis with ascites 28.6 ng/h, severe hepatocellular dysfunction 57.5 ng/h), but normal in compensated liver disease (6.7 ng/h). In the early stages of hepatorenal syndrome, leukotriene E4 excretion rate was up to 100-fold higher (560 ng/h) than in normals, and fell in parallel with creatinine clearance, indicative of the glomerular filtration rate-dependent renal excretion. Following correction for creatinine clearance, leukotriene E4, excretion was considerably higher in hepatorenal syndrome (54.1 pg/ml creatinine clearance) compared with normals (1.0 pg/ml creatinine clearance), chronic renal failure (3.2 pg/ml creatinine clearance), decompensated liver disease (ascites 7.7 pg/ml creatinine clearance, and severe hepatocellular dysfunction 11.0 pg/ml creatinine clearance), and compensated liver disease (1.9 pg/ml creatinine clearance). To interpret the significance of these findings, we determined renal clearance and endogenous metabolism of the cysteinyl leukotrienes by infusion of [3H]leukotriene C4 into a single subject with hepato-renal syndrome and two control subjects. Renal clearance of leukotriene E4, was reduced in hepatorenal syndrome (2.4 ml/min) compared with controls (greater than 17 ml/min) which together with the increased excretion rate of leukotriene E4 demonstrates that there is increased cysteinyl leukotriene production in hepatorenal syndrome. This may be one of the factors involved in its pathogenesis.

Adolescent↗
PubMed1990

Tissue concentrations of MPTP and MPP+ after administration of lethal and sublethal doses of MPTP to mice.

Tissue concentrations of MPP+ (1-methyl-4-phenylpyridinium) were measured in Charles River CFW mice after administration of high doses of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) or MPP+ given subcutaneously or orally, to investigate the relationships between tissue concentrations and lethality resulting from these compounds. MPTP given subcutaneously led to much higher concentrations of MPP+ in brain and somewhat higher concentrations of MPP+ in peripheral tissues than did MPTP given orally. MPTP caused no lethality at oral doses up to 160 mg/kg whereas subcutaneous MPTP had an LD50 of 54 mg/kg. Deprenyl pretreatment antagonized the lethality of subcutaneous MPTP and reduced MPP+ concentrations in brain and in other tissues after MPTP injection. Deprenyl caused a greater and longer-lasting inhibition of MPTP oxidation than of phenylethylamine oxidation, especially in liver, although both compounds are thought to be oxidized by monoamine oxidase type B. The protective effect of deprenyl against MPTP lethality implicates MPP+ (or possibly some other metabolite) in the lethality after MPTP injection. The reduced lethality of MPTP when given orally and the relative lack of brain levels of MPTP or MPP+ after oral MPTP implicate the brain as a target organ in the lethality of MPTP. Lethality after MPP+ administration almost certainly does not involve the brain, since little or no MPP+ could be measured in brain after oral or subcutaneous dosing of MPP+.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

Serotonin uptake and serotonin uptake inhibition.

Serotonin uptake carriers occur on serotonin neurons, on glial cells and on blood platelets. The uptake carrier on serotonin neurons inactivates serotonin that has been released into the synaptic cleft by transporting it back into the nerve terminal. The serotonin uptake carrier is the means by which blood platelets acquire serotonin, since they do not synthesize it. The function of the serotonin uptake carrier on glial cells is poorly understood. Selective inhibitors of serotonin uptake enhance neurotransmission via serotonergic neurons and have been useful pharmacologic tools for studying physiologic roles of serotonin neurons. Some serotonin uptake inhibitors are finding therapeutic uses in mental depression and other psychiatric disorders and in treating obesity and bulimia; other therapeutic applications continue to be evaluated.

Animals↗
PubMed1990

Femur length in the US prediction of trisomy 21 and other chromosomal abnormalities.

After review of 461 consecutive amniocentesis examinations, 428 fetuses with normal karyotype and 13 with chromosomal abnormalities were analyzed. Six of the abnormal fetuses had trisomy 21, and seven had other chromosomal abnormalities. The ratio of measured-to-expected femur length (MFL/EFL) was determined for each fetus. The MFL/EFL values were 1.0 +/- 0.7 (mean +/- standard deviation) for the control group, 0.94 +/- 0.06 for trisomy 21 fetuses, 0.94 +/- 0.10 for non-trisomy 21 fetuses, and 0.94 +/- 0.08 for the entire group of fetuses with chromosomal abnormalities. The mean MFL/EFL value for the abnormal fetuses differed significantly from that for the control group (P less than .003). An MFL/EFL of 0.90 or less resulted in a sensitivity of 46.2% and a specificity of 94.1% for detection of all chromosomal abnormalities. For detecting trisomy 21, the sensitivity and specificity were 50% and 93.5%, respectively. Assuming a pretest probability for trisomy 21 of one in 250, an MFL/EFL of 0.90 or less resulted in a positive predictive value of 3%. It is concluded that an MFL/EFL of less than 0.90 modifies the relative risk for chromosomal abnormalities and may significantly influence the decision for amniocentesis.

Chromosome Aberrations↗
PubMed1990

Ventilatory effects of substance P, vasoactive intestinal peptide, and nitroprusside in humans.

Animal studies suggest that the neuropeptides, substance P and vasoactive intestinal peptide (VIP), may influence carotid body chemoreceptor activity and that substance P may take part in the carotid body response to hypoxia. The effects of these peptides on resting ventilation and on ventilatory responses to hypoxia and to hypercapnia have been investigated in six normal humans. Infusions of substance P (1 pmol.kg-1.min-1) and of VIP (6 pmol.kg-1.min-1) were compared with placebo and with nitroprusside (5 micrograms.kg-1.min-1) as a control for the hypotensive action of the peptides. Both peptides caused significantly less hypotension than nitroprusside. Substance P and nitroprusside caused significantly greater increases in ventilation and in the hypoxic ventilatory response than VIP. No changes were seen in hypercapnic sensitivity. The stimulation of ventilation and the differential effects on ventilatory chemosensitivity that accompanied hypotension are consistent either with stimulation of carotid body chemoreceptor activity or with an interaction with peripheral chemoreceptor input to the respiratory center, as is seen in animals. The similar cardiovascular but different ventilatory effects of the peptides suggest that substance P may also stimulate the carotid body in a manner independent of the effect of hypotension. This is consistent with a role of substance P in the hypoxic ventilatory response in humans.

Adult↗
PubMed1990

Urinary N tau-methylimidazole acetic acid excretion in respiratory disease.

N tau-methylimidazole acetic acid (N tau-MIAA) is the principal urinary metabolite of histamine. The basal urinary excretion rate of N tau-MIAA was determined as 0.117 +/- 0.008 (SE) mg/h, with a renal clearance for N tau-MIAA of 273 +/- 27 ml/min implying active secretion. After subpharmacological infusion of histamine (50 ng.kg-1.min-1 over 2 h) in five volunteers that increased plasma histamine from 0.28 +/- 0.04 to 0.71 +/- 0.15 ng/ml, urinary excretion of N tau-MIAA over 8 h was increased by less than 17% compared with a control saline infusion. Urinary N tau-MIAA excretion in normal controls (273 +/- 14 micrograms/mmol creatinine) was similar to that observed in patients with severe acute asthma (253 +/- 22 micrograms/mmol), antigen-induced bronchoconstriction (269 +/- 21 micrograms/mmol), seasonal allergic rhinitis (304 +/- 31 micrograms/mmol), and clinically stable bronchiectasis (270 +/- 22 micrograms/mmol). In contrast, large increases in metabolite excretion (greater than 7,000 micrograms/mmol creatinine) were observed in a patient with systemic mastocytosis where very high plasma histamine levels were recorded (greater than 500 ng/ml) and marked systemic hemodynamic effects occurred. We conclude that urinary N tau-MIAA will only be increased in pathologies where sustained hyperhistaminemia occurs and that increased local histamine production in the lung or the upper airway does not cause a measurable change in the basal urinary excretion of this metabolite.

Adult↗
PubMed1990

Serotonin receptor subtypes involved in the elevation of serum corticosterone concentration in rats by direct- and indirect-acting serotonin agonists.

The serum corticosterone concentration in rats was increased by injection of quipazine, a relatively nonselective serotonin (5-hydroxytryptamine; 5-HT) agonist, or 8-hydroxy-2-(di-n- propylamino)tetralin (8-OH-DPAT), a serotonin agonist selective for the 5-HT1A subtype of receptor. The quipazine-induced increase in serum corticosterone was antagonized by 17 different serotonin antagonists; of these, MDL 11939, pirenperone, setoperone, mianserin, LY 281067, ketanserin, ritanserin and clozapine have relatively selective affinity for the 5-HT2 subtype of receptor. The 8-OH-DPAT-induced increase in serum corticosterone was not antagonized by metergoline, the most potent antagonist of the quipazine effect, but was antagonized by pindolol or penbutolol, 5-HT1A receptor antagonists. Pindolol did not block the effect of quipazine. The results support earlier evidence that serum corticosterone concentration in rats can be increased by activation of either 5-HT1A or 5-HT2 receptors. Indirect-acting serotonin agonists - fluoxetine, L-5-hydroxytryptophan and p-chloroamphetamine - also increased serum corticosterone concentrations. The increases elicited by those agents, which earlier had been reported not to be blocked by metergoline pretreatment, also were not blocked by pretreatment with pindolol or with the combination of metergoline and pindolol. Thus, an involvement of a specific serotonin receptor subtype in the actions of these indirect agonists has not been established.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

Fluoxetine and its two enantiomers as selective serotonin uptake inhibitors.

The biochemical and pharmacological profiles of R,S-fluoxetine and its R and S enantiomers have been compared and reviewed. Both enantiomers exhibit profiles analogous to R,S-fluoxetine as inhibitors of serotonin uptake in vitro and in vivo with about equal potencies or a eudismic ratio near unity.

Animals↗
PubMed1990

The effect of sulindac on the abnormal cough reflex associated with dry cough.

In order to determine the possible role of prostaglandins in the abnormal cough reflex in patients with dry cough, the effects of a cyclooxygenase inhibitor on cough symptoms were examined. This was measured by a cough symptom score and by the cough reflex sensitivity to inhaled capsaicin in a double blind, randomized, cross-over study comparing the effects of placebo with sulindac, 200 mg daily for 1 week. We studied six hypertensive patients with angiotensin converting enzyme inhibitor-associated cough and six patients with an idiopathic, dry, unproductive cough, all of whom had an increase in the sensitivity of the cough reflex. There was no change in blood pressure control in the hypertensive patients during sulindac therapy. The patients with the angiotensin converting enzyme-associated cough had a significant reduction in the cough symptom score and also a significant increase in the dose of capsaicin causing two or more coughs (threshold sensitivity) and that causing five or more coughs (near maximum response) during sulindac therapy as compared to placebo. In those patients with idiopathic, dry, unproductive cough, sulindac did not alter the symptom of cough or the cough reflex response to capsaicin. These results suggest that prostaglandins may be involved in cough associated with angiotensin converting enzyme inhibitor therapy, but are less likely to be important in the pathogenesis of more common dry coughs of unknown cause.

Aged↗
PubMed1990

Effects of nonsteroidal anti-inflammatory drugs on the bronchial hyperresponsiveness of middle-aged male smokers.

Bronchial hyperresponsiveness (BHR) in smokers is believed to be a consequence of airway wall inflammation. We have examined the effects of treatment with nonsteroidal anti-inflammatory drugs (NSAID) on BHR to inhaled histamine, measured as the provocative concentration reducing forced expiratory volume in one second (FEV1) by 20% (PC20), in middle-aged male cigarette smokers in two separate double-blind, placebo-controlled, cross-over trials. Baseline FEV1 in these smokers ranged from 41-117% predicted values. In the first study 15 men (mean age 58 yrs, FEV1 2.20 l) were examined before and one hour after a single dose of 1.2 g aspirin. There was no significant change in PC20 (geometric mean 1.88 mg.ml-1 pre-aspirin, 1.89 mg.ml-1 post-aspirin) or baseline FEV1 and we observed no tachyphylaxis to the effects of inhaled histamine at one hour after placebo. In the second study 10 men (mean age 60 yrs, FEV1 2.53 l) were examined before and after three days' treatment with the NSAID flurbiprofen 50 mg t.d.s. Baseline PC20 was higher in this group than in the first study. There was no relationship between the excretion of urinary thromboxane metabolites and the intensity of BHR under baseline conditions; flurbiprofen greatly reduced the urinary excretion of thromboxane metabolites, but baseline FEV1 was not altered. Analysis of change in PC20 was complicated by a difference in baseline PC20 before the two treatments, but treatment with flurbiprofen did not significantly attenuate BHR. The results suggest that thromboxane or other cyclo-oxygenase products of arachidonic acid metabolism do not play an important role in the short-term maintenance of BHR to histamine in middle-aged male cigarette smokers.

Aged↗
PubMed1990

Separation of cough and reflex bronchoconstriction by inhaled local anaesthetics.

Cough and airway constriction are common features of respiratory diseases. Both can be caused by stimulation of airway nerves. We have studied the effects of airway anaesthesia on these reflexes, stimulated by inhaled capsaicin, in order to determine whether they are controlled by the same sensory nerves. Ten volunteers had capsaicin cough dose responses performed before and at 10 min after inhaling placebo (ascorbic acid in saline), and the topical anaesthetics lignocaine 40 mg, and dyclonine 8 and 4 mg. The effect of the drugs on respiratory resistance (Rrs), measured using a forced oscillation technique, was measured both before and after the inhalation of a dose of capsaicin which caused less than two coughs. Lignocaine (40 mg) and dyclonine (8 mg) caused significant reports of oral anaesthesia but only lignocaine reduced the cough response to inhaled capsaicin, increasing the log dose of capsaicin causing three or more coughs by 162%. None of the treatments altered basal Rrs or its increase after inhaled capsaicin. Thus, the cough and reflex bronchoconstriction caused by inhaled capsaicin have different sensitivities to inhaled local anaesthesia, suggesting that the effect may be mediated by different sensory pathways.

Administration, Inhalation↗
PubMed1989

Determination of brain concentrations of 8-hydroxy-2-(di-n-propylamino)tetralin by liquid chromatography with electrochemical detection.

A liquid chromatographic method using electrochemical detection is described for the assay of brain concentrations of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), centrally acting serotonin agonists selective for the 5HT-1A subtype of serotonin receptors. The method is sensitive to approximately 5 ng/g concentrations. After a 1mg/kg s.c. dose of 8-OH-DPAT in rats, its concentration in whole brain declined rapidly during the first 4 hr with a half-life of 26 min. At 30 min after a 1 mg/kg s.c. dose of 8-OH-DPAT, concentrations were approximately equal in hypothalamus, striatum, hippocampus, cerebellum and brain stem but were slightly lower in midbrain. 8-OH-DPAT disappeared from hypothalamus, midbrain and hippocampus at similar rates during the first 90 min after a 1 mg/kg s.c dose. Concentrations of 8-OH-DPAT in whole brain were markedly higher after s.c. than after i.p. administration of 8-OH-DPAT, consistent with earlier data showing 8-OH-DPAT to be more potent when given s.c. than when given i.p. in decreasing brain concentrations of 5-hydroxyindoleacetic acid. Pretreatment with proadifen (SKF-525A), an inhibitor of microsomal drug metabolism, slightly increased brain concentrations of 8-OH-DPAT. Pindolol, which antagonized the elevation of serum corticosterone concentration by 8-OH-DPAT, did not alter brain concentrations of 8-OH-DPAT. The analytical method should be useful in correlating brain concentrations of 8-OH-DPAT with various neurochemical, behavioral or other functional effects that have been described for this compound.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

AIDS-antiviral sulfolipids from cyanobacteria (blue-green algae).

A recently developed tetrazolium-based microculture assay was used to screen extracts of cultured cyanobacteria (blue-green algae) for inhibition of the cytopathic effects of the human immunodeficiency virus (HIV-1), which is implicated as a causative agent of AIDS. A number of extracts were found to be remarkably active against the AIDS virus. A new class of HIV-1-inhibitory compounds, the sulfonic acid-containing glycolipids, was discovered through the use of the microculture assay to guide the fractionation and purification process. The pure compounds were active against HIV-1 in cultured human lymphoblastoid CEM, MT-2, LDV-7, and C3-44 cell lines in the tetrazolium assay as well as in p24 viral protein and syncytium formation assays.

Antiviral Agents↗
PubMed1989

Change in cough reflex after treatment with enalapril and ramipril.

OBJECTIVE: To find out whether enalapril or ramipril causes the sensitivity of the cough reflex to change or symptomatic cough to develop in patients with hypertension. DESIGN: Prospective, placebo controlled, double blind, randomised crossover study. SETTING: Academic units of clinical pharmacology and medicine. PATIENTS: 20 Patients (nine men and 11 women) who needed to take angiotensin converting enzyme inhibitors to control hypertension. INTERVENTIONS: All patients received enalapril 10 mg daily, ramipril 10 mg daily, or placebo daily for one week in random order, with a washout period of at least one week between treatments. For assessment of sensitivity of the cough reflex the patients inhaled various concentrations of capsaicin solution in random order. MAIN OUTCOME MEASURES: Measurement of the doses of capsaicin required to cause two or more and five or more coughs or the development of a symptomatic cough. RESULTS: Blood pressure, symptoms of cough, and the sensitivity of the cough reflex to inhaled capsaicin were recorded at the start of the study and before and at the end of each treatment period. Plasma urea and creatinine concentrations and angiotensin converting enzyme activity were measured at the start of the study and the end of each treatment period. Data were analysed by two way analysis of variance. Mean blood pressure was 159/97 mm Hg at the start of the study and 152/92, 143/88, and 147/86 mm Hg after treatment with placebo, enalapril, and ramipril respectively. Mean (SE) plasma angiotensin converting enzyme activity was 2.2 (0.2) mmol/l/h after treatment with placebo and fell significantly to 1.3 (0.1) mmol/l/h and to 0.4 (0.1) mmol/l/h after treatment with enalapril and ramipril respectively. No patient complained of cough while taking placebo but three women complained of cough when taking both enalapril and ramipril. The mean (95% confidence interval) lowest dose of capsaicin causing two or more coughs was 2.4 (1.5 to 4.0), 1.8 (1.12 to 2.82), and 2.2 (1.7 to 3.0) nmol after treatment with placebo, enalapril, and ramipril respectively; none of these changes were significant. The lowest dose of capsaicin causing five or more coughs was 18.9 (13.9 to 25.8), 14.4 (8.4 to 24.5), and 15.3 (10.8 to 21.2) nmol respectively; none of these changes were significant. The three patients who complained of cough had normal sensitivity to capsaicin after treatment with placebo but had a considerably increased sensitivity after treatment with enalapril and ramipril. CONCLUSIONS: Both enalapril and ramipril increase the sensitivity of the cough reflex appreciably in patients who complain of cough during treatment, but they do not change the se

Adult↗
PubMed1989

Urinary leukotriene E4 after antigen challenge and in acute asthma and allergic rhinitis.

The leukotrienes LTC4, D4, and E4 are potent bronchoconstrictor agents and are thought to have an important role in asthma. Urinary LTE4, a stable urinary end-product of LTC4 and LTD4, was measured, by means of high-performance liquid chromatography and radioimmunoassay. LTE4 excretion followed a log-normal distribution in twenty-nine healthy controls, with a geometric mean of 23.8 (95% confidence interval 19.9-28.2) ng/mmol creatinine. Urine was collected from eight atopic subjects for 3 h after antigen inhalation and a control urine collection was made a week later at the same time of day. Urinary LTE4 was significantly higher after antigen challenge than in the control sample (153.7 [87.1-271.3] vs 23.5 [13.7-69.5] ng/mmol creatinine; p less than 0.01). Urinary LTE4 was also measured in twenty patients with severe acute asthma and nine patients with seasonal allergic rhinitis. Mean urinary LTE4 was higher in the asthmatic patients (78.3 [46.5-131.8] ng/mmol creatinine) than in normal subjects (p less than 0.01), although there was substantial overlap into the normal range. The urinary LTE4 values of the rhinitis patients were within the normal range whether or not they had symptoms. LTC4 and LTD4 were also found in bronchoalveolar lavage fluid from one of the three atopic subjects challenged with antigen before lavage, and in a single patient who underwent lavage after admission with severe acute asthma. These studies provide evidence that leukotrienes are released in vivo in man after antigen challenge and in acute asthma.

Acute Disease↗